Cysteine induces mitochondrial reductive stress in glioblastoma through hydrogen peroxide production.

Glucose and amino acid metabolism are critical for glioblastoma (GBM) growth, but little is known about the specific metabolic alterations in GBM that are targetable with FDA-approved compounds. To investigate tumor metabolism signatures unique to GBM, we interrogated The Cancer Genome Atlas for alterations in glucose and amino acid signatures in GBM relative to other human cancers and found that GBM exhibits the highest levels of cysteine and methionine pathway gene expression of 32 human cancers. Treatment of patient-derived GBM cells with the FDA-approved single cysteine compound N-acetylcysteine (NAC) reduced GBM cell growth and mitochondrial oxygen consumption, which was worsened by glucose starvation. Normal brain cells and other cancer cells showed no response to NAC. Mechanistic experiments revealed that cysteine compounds induce rapid mitochondrial H2O2 production and reductive stress in GBM cells, an effect blocked by oxidized glutathione, thioredoxin, and redox enzyme overexpression. From analysis of the clinical proteomic tumor analysis consortium (CPTAC) database, we found that GBM cells exhibit lower expression of mitochondrial redox enzymes than four other cancers whose proteomic data are available in CPTAC. Knockdown of mitochondrial thioredoxin-2 in lung cancer cells induced NAC susceptibility, indicating the importance of mitochondrial redox enzyme expression in mitigating reductive stress. Intraperitoneal treatment of mice bearing orthotopic GBM xenografts with a two-cysteine peptide induced H2O2 in brain tumors in vivo. These findings indicate that GBM is uniquely susceptible to NAC-driven reductive stress and could synergize with glucose-lowering treatments for GBM.

DNA G-Quadruplex Is a Transcriptional Control Device That Regulates Memory.

The conformational state of DNA fine-tunes the transcriptional rate and abundance of RNA. Here, we report that G-quadruplex DNA (G4-DNA) accumulates in neurons, in an experience-dependent manner, and that this is required for the transient silencing and activation of genes that are critically involved in learning and memory in male C57/BL6 mice. In addition, site-specific resolution of G4-DNA by dCas9-mediated deposition of the helicase DHX36 impairs fear extinction memory. Dynamic DNA structure states therefore represent a key molecular mechanism underlying memory consolidation.One-Sentence Summary: G4-DNA is a molecular switch that enables the temporal regulation of the gene expression underlying the formation of fear extinction memory.

Mertk-expressing microglia influence oligodendrogenesis and myelin modelling in the CNS.

BACKGROUND: Microglia, an immune cell found exclusively within the CNS, initially develop from haematopoietic stem cell precursors in the yolk sac and colonise all regions of the CNS early in development. Microglia have been demonstrated to play an important role in the development of oligodendrocytes, the myelin producing cells in the CNS, as well as in myelination. Mertk is a receptor expressed on microglia that mediates immunoregulatory functions, including myelin efferocytosis. FINDINGS: Here we demonstrate an unexpected role for Mertk-expressing microglia in both oligodendrogenesis and myelination. The selective depletion of Mertk from microglia resulted in reduced oligodendrocyte production in early development and the generation of pathological myelin. During demyelination, mice deficient in microglial Mertk had thinner myelin and showed signs of impaired OPC differentiation. We established that Mertk signalling inhibition impairs oligodendrocyte repopulation in Xenopus tadpoles following demyelination. CONCLUSION: These data highlight the importance of microglia in myelination and are the first to identify Mertk as a regulator of oligodendrogenesis and myelin ultrastructure.

Dopamine D1R-neuron cacna1c deficiency: a new model of extinction therapy-resistant post-traumatic stress.

Post-traumatic stress disorder (PTSD) is characterized by persistent fear memory of remote traumatic events, mental re-experiencing of the trauma, long-term cognitive deficits, and PTSD-associated hippocampal dysfunction. Extinction-based therapeutic approaches acutely reduce fear. However, many patients eventually relapse to the original conditioned fear response. Thus, understanding the underlying molecular mechanisms of this condition is critical to developing new treatments for patients. Mutations in the neuropsychiatric risk gene CACNA1C, which encodes the Cav1.2 isoform of the L-type calcium channel, have been implicated in both PTSD and highly comorbid neuropsychiatric conditions, such as anxiety and depression. Here, we report that male mice with global heterozygous loss of cacna1c exhibit exacerbated contextual fear that persists at remote time points (up to 180 days after shock), despite successful acute extinction training, reminiscent of PTSD patients. Because dopamine has been implicated in contextual fear memory, and Cav1.2 is a downstream target of dopamine D1-receptor (D1R) signaling, we next generated mice with specific deletion of cacna1c from D1R-expressing neurons (D1-cacna1cKO mice). Notably, D1-cacna1cKO mice also show the same exaggerated remote contextual fear, as well as persistently elevated anxiety-like behavior and impaired spatial memory at remote time points, reminiscent of chronic anxiety in treatment-resistant PTSD. We also show that D1-cacna1cKO mice exhibit elevated death of young hippocampal neurons, and that treatment with the neuroprotective agent P7C3-A20 eradicates persistent remote fear. Augmenting survival of young hippocampal neurons may thus provide an effective therapeutic approach for promoting durable remission of PTSD, particularly in patients with CACNA1C mutations or other genetic aberrations that impair calcium signaling or disrupt the survival of young hippocampal neurons.

Correction: Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.

A correction to this paper has been published and can be accessed via a link at the top of the paper.

Cocaine- and stress-primed reinstatement of drug-associated memories elicit differential behavioral and frontostriatal circuit activity patterns via recruitment of L-type Ca2+ channels.

Cocaine-associated memories are critical drivers of relapse in cocaine-dependent individuals that can be evoked by exposure to cocaine or stress. Whether these environmental stimuli recruit similar molecular and circuit-level mechanisms to promote relapse remains largely unknown. Here, using cocaine- and stress-primed reinstatement of cocaine conditioned place preference to model drug-associated memories, we find that cocaine drives reinstatement by increasing the duration that mice spend in the previously cocaine-paired context whereas stress increases the number of entries into this context. Importantly, both forms of reinstatement require Cav1.2 L-type Ca2+ channels (LTCCs) in cells of the prelimbic cortex that project to the nucleus accumbens core (PrL→NAcC). Utilizing fiber photometry to measure circuit activity in vivo in conjunction with the LTCC blocker, isradipine, we find that LTCCs drive differential recruitment of the PrL→ NAcC pathway during cocaine- and stress-primed reinstatement. While cocaine selectively activates PrL→NAcC cells prior to entry into the cocaine-paired chamber, a measure that is predictive of duration in that chamber, stress increases persistent activity of this projection, which correlates with entries into the cocaine-paired chamber. Using projection-specific chemogenetic manipulations, we show that PrL→NAcC activity is required for both cocaine- and stress-primed reinstatement, and that activation of this projection in Cav1.2-deficient mice restores reinstatement. These data indicate that LTCCs are a common mediator of cocaine- and stress-primed reinstatement. However, they engage different patterns of behavior and PrL→NAcC projection activity depending on the environmental stimuli. These findings establish a framework to further study how different environmental experiences can drive relapse, and supports further exploration of isradipine, an FDA-approved LTCC blocker, as a potential therapeutic for the prevention of relapse in cocaine-dependent individuals.

Relationship between visual acuity and spectral domain optical coherence tomography retinal parameters in neovascular age-related macular degeneration.

PURPOSE: Relationship between spectral domain optical coherence tomography (SD-OCT) and visual acuity (VA) in neovascular age-related macular degeneration (NVAMD). PROCEDURES: VA and SD-OCTs of 64 treatment-naive eyes with NVAMD were retrospectively collected at baseline and 1 year (n = 30). Retinal and subretinal spaces were manually analyzed. Volume and thickness measurements were correlated with VA. RESULTS: At baseline, lower VA correlated with increased volume of subretinal hyperreflective material (R = 0.4, p < 0.001) and with decreased volume of the photoreceptor layer (PRL, R = -0.4, p < 0.01). At 1 year, lower VA correlated with decreased volume of the retina (R = -0.7, p < 0.001), outer nuclear layer (R = -0.6, p < 0.05) and PRL (R = -0.7, p < 0.001). Decrease in VA after 1 year correlated with a decrease in PRL (R = 0.4, p < 0.05). CONCLUSIONS: Quantitative analysis of SD-OCT revealed correlations between VA and retinal and subretinal morphological changes in NVAMD. MESSAGE: Atrophy of the outer retina is an important correlate for lower VA in NVAMD.

Sugar-free synapses run on mitochondrial Sirtuin 3.

Metabolic plasticity of neurons ensures their activity continues when glucose is limited. Walsh and Simon discuss new work by Ashrafi and colleagues (https://doi.org/10.1083/jcb.202305048) that finds Sirtuin 3 directs local metabolic adaptation at synapses during sustained glucose deprivation.

Different phenotypes of the appearance of the outer plexiform layer on optical coherence tomography.

PURPOSE: To present a selected case series of different phenotypes of the normal outer plexiform layer (OPL) visualized by optical coherence tomography (OCT). METHODS: Five cases were selected to represent the spectrum of appearances of the OPL in this case series. Categorical descriptions of each manifestation were then developed. Additional SD-OCT scans were obtained from a normal volunteer to further support the hypothesis. RESULTS: The inner one-third of the OPL typically appears hyperreflective on OCT, while the outer two-thirds (Henle fiber layer) may have a more varied appearance. Six different phenotypes of Henle fiber layer reflectivity were noted in this series, and classified as: bright, columnar, dentate, delimited, indistinct, and dark. The brightness of the Henle fiber layer appears to depend on the geometric angle between the OCT light beam and the axonal fibers in this portion of the OPL. This angle appears to be a function of the natural orientation of the Henle fiber layer tissue (θN), the existence of subretinal pathology that alters the angle of the neurosensory retina (θ(P)), and the tilt angle of the tissue on the B-scan (θ(T)) due to decentered OCT acquisition. CONCLUSIONS: Since accurate interpretation of the OPL/ONL boundary is of vital importance to study the thickness of ONL, location of cystoid lesions, hyperreflective crescents over drusen, et al., our case series may aid better understanding of the OPL appearance in SD-OCT. In the absence of clear delineation, it may be most correct to refer to indistinct OPL and ONL together as the photoreceptor nuclear axonal complex (PNAC).

Evaluation of the axial location of cystoid spaces in retinal vein occlusion using optical coherence tomography.

PURPOSE: To analyze the axial distribution of intraretinal cystoid changes in patients with retinal vein occlusion (RVO), incorporating a new hypothesis about the optical coherence tomographic boundary between the outer nuclear layer and the outer plexiform layer. METHODS: Data were collected from patients with RVO who underwent spectral domain coherence tomography imaging. For each image set, certified graders evaluated each retinal layer for cystoid macular edema, defined as hyporeflective intraretinal cystoid spaces. Subretinal fluid, if present, was also noted. RESULTS: Forty-eight eyes were evaluated (24 branch RVO, 18 central RVO, 6 hemiretinal vein occlusion). Cystoid macular edema was present in 30.8% of eyes in outer nuclear layer, 77.9 % in outer plexiform layer, 77.9 % in inner nuclear layer, 36.9 % in inner plexiform layer, 48.8 % in ganglion cell layer, and 4.9% in nerve fiber layer. Subretinal fluid was assessed as present in 23.8% of patients. The presence of subretinal fluid correlated most strongly with cystoid changes in the outer nuclear layer (r = 0.514, P = 0.001) but was not significantly correlated with these changes in the superficial retina. CONCLUSION: Use of spectral domain coherence tomography allows precise characterization of the axial location of cystoid spaces in RVO and highlights the frequency of fluid accumulation in the outer plexiform layer and inner nuclear layer. Using updated definitions, cystoid macular edema seems to occur less frequently in the outer nuclear layer, but when it does so, it is often associated with subretinal fluid. Future longitudinal studies, documenting the axial progression of such changes, and their response to treatment, may be of clinical relevance as pharmacotherapeutic options evolve.

Mouse microglia express unique miRNA-mRNA networks to facilitate age-specific functions in the developing central nervous system.

Microglia regulate multiple processes in the central nervous system, exhibiting a considerable level of cellular plasticity which is facilitated by an equally dynamic transcriptional environment. While many gene networks that regulate microglial functions have been characterised, the influence of epigenetic regulators such as small non-coding microRNAs (miRNAs) is less well defined. We have sequenced the miRNAome and mRNAome of mouse microglia during brain development and adult homeostasis, identifying unique profiles of known and novel miRNAs. Microglia express both a consistently enriched miRNA signature as well as temporally distinctive subsets of miRNAs. We generated robust miRNA-mRNA networks related to fundamental developmental processes, in addition to networks associated with immune function and dysregulated disease states. There was no apparent influence of sex on miRNA expression. This study reveals a unique developmental trajectory of miRNA expression in microglia during critical stages of CNS development, establishing miRNAs as important modulators of microglial phenotype.

Regulation of social interaction in mice by a frontostriatal circuit modulated by established hierarchical relationships.

Social hierarchies exert a powerful influence on behavior, but the neurobiological mechanisms that detect and regulate hierarchical interactions are not well understood, especially at the level of neural circuits. Here, we use fiber photometry and chemogenetic tools to record and manipulate the activity of nucleus accumbens-projecting cells in the ventromedial prefrontal cortex (vmPFC-NAcSh) during tube test social competitions. We show that vmPFC-NAcSh projections signal learned hierarchical relationships, and are selectively recruited by subordinate mice when they initiate effortful social dominance behavior during encounters with a dominant competitor from an established hierarchy. After repeated bouts of social defeat stress, this circuit is preferentially activated during social interactions initiated by stress resilient individuals, and plays a necessary role in supporting social approach behavior in subordinated mice. These results define a necessary role for vmPFC-NAcSh cells in the adaptive regulation of social interaction behavior based on prior hierarchical interactions.

miRNAs in Microglia: Important Players in Multiple Sclerosis Pathology.

Microglia are the resident immune cells of the central nervous system and important regulators of brain homeostasis. Central to this role is a dynamic phenotypic plasticity that enables microglia to respond to environmental and pathological stimuli. Importantly, different microglial phenotypes can be both beneficial and detrimental to central nervous system health. Chronically activated inflammatory microglia are a hallmark of neurodegeneration, including the autoimmune disease multiple sclerosis (MS). By contrast, microglial phagocytosis of myelin debris is essential for resolving inflammation and promoting remyelination. As such, microglia are being explored as a potential therapeutic target for MS. MicroRNAs (miRNAs) are short non-coding ribonucleic acids that regulate gene expression and act as master regulators of cellular phenotype and function. Dysregulation of certain miRNAs can aberrantly activate and promote specific polarisation states in microglia to modulate their activity in inflammation and neurodegeneration. In addition, miRNA dysregulation is implicated in MS pathogenesis, with circulating biomarkers and lesion specific miRNAs identified as regulators of inflammation and myelination. However, the role of miRNAs in microglia that specifically contribute to MS progression are still largely unknown. miRNAs are being explored as therapeutic agents, providing an opportunity to modulate microglial function in neurodegenerative diseases such as MS. This review will focus firstly on elucidating the complex role of microglia in MS pathogenesis. Secondly, we explore the essential roles of miRNAs in microglial function. Finally, we focus on miRNAs that are implicated in microglial processes that contribute directly to MS pathology, prioritising targets that could inform novel therapeutic approaches to MS.

Identification and Characterisation of cis-Regulatory Elements Upstream of the Human Receptor Tyrosine Kinase Gene MERTK.

BACKGROUND: MERTK encodes a receptor tyrosine kinase that regulates immune homeostasis via phagocytosis of apoptotic cells and cytokine-mediated immunosuppression. MERTK is highly expressed in the central nervous system (CNS), specifically in myeloid derived innate immune cells and its dysregulation is implicated in CNS pathologies including the autoimmune disease multiple sclerosis (MS). OBJECTIVE: While the cell types and tissues that express MERTK have been well described, the genetic elements that define the gene's promoter and regulate specific transcription domains remain unknown. The primary objective of this study was to define and characterise the human MERTK promoter region. METHODS: We cloned and characterized the 5' upstream region of MERTK to identify cis-acting DNA elements that promote gene transcription in luciferase reporter assays. In addition, promoter regions were tested for sensitivity to the anti-inflammatory glucocorticoid dexamethasone. RESULTS: This study identified identified both proximal and distal-acting DNA elements that promote transcription. The strongest promoter activity was identified in an ∼850 bp region situated 3 kb upstream of the MERTK transcription start site. Serial deletions of this putative enhancer revealed that the entire region is essential for expression activity. Using in silico analysis, we identified several candidate transcription factor binding sites. Despite a well-established upregulation of MERTK in response to anti-inflammatory glucocorticoids, no DNA region within the 5 kb putative promoter was found to directly respond to dexamethasone treatment. CONCLUSIONS: Elucidating the genetic mechanisms that regulate MERTK expression gives insights into gene regulation during homeostasis and disease, providing potential targets for therapeutic modulation of MERTK transcription.

Relationship between optical coherence tomography retinal parameters and visual acuity in diabetic macular edema.

PURPOSE: To investigate the relationship between optical coherence tomography (OCT)-derived measurements of retinal morphology and visual acuity in patients with diabetic macular edema. DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 67 consecutive patients (67 eyes) with diabetic macular edema (DME) who underwent Stratus OCT imaging (Carl Zeiss Meditec, Inc., Dublin, CA). METHODS: Best-corrected Snellen visual acuity was recorded for each patient. Raw exported Stratus OCT images for each patient were analyzed using custom software entitled "OCTOR," which allows the precise positioning of prespecified boundaries on individual B-scans. Thickness, volume, and intensity were calculated for neurosensory retina and subretinal fluid. In addition, photoreceptor outer segment (POS) thickness was quantified. MAIN OUTCOME MEASURES: Optical coherence tomography-derived measurements of retinal morphology and visual acuity. RESULTS: The Spearman coefficient values (r) of the correlation between OCTOR-derived measurements of central subfield thickness, intensity, subretinal fluid volume, and POS thickness and the logarithm of the minimum angle of resolution visual acuities were 0.3428 (P = 0.005), -0.2658 (P = 0.03), -0.2683 (P = 0.38), and -0.3703 (P = 0.002), respectively. Multivariate models with stepwise selection revealed a cumulative R(2) of 0.4305 in the total study population, with R(2) of 0.4999 and 0.7628 in the untreated and prior focal laser groups, respectively. CONCLUSIONS: Subanalysis and quantification of OCT features in eyes with DME seem to be of value. In particular, POS thickness seems to be an important predictor of function and visual acuity in patients with DME.

Relationship between angiographic and optical coherence tomographic (OCT) parameters for quantifying choroidal neovascular lesions.

BACKGROUND: To correlate the volume of various spaces on optical coherence tomography (OCT) with fluorescein angiographic (FA) parameters in neovascular age-related macular degeneration (AMD). METHODS: Sixty-five consecutive cases of active subfoveal choroidal neovascularization (CNV) associated with AMD were retrospectively collected. Area and greatest linear dimension of CNV lesion components were calculated on FA. Corresponding StratusOCT image sets were analyzed using custom software (termed OCTOR), which allows manual measurement of the volume of the neurosensory retina, subretinal fluid, subretinal tissue, and pigment epithelial detachment (PED). RESULTS: Area of occult CNV on FA correlated with PED (R = 0.62) and subretinal fluid (R = 0.28) volume and negatively with subretinal tissue volume (R = -0.26) on OCT. Area of classic CNV on FA correlated with subretinal tissue (R = 0.60) and retinal (R = 0.38) volume on OCT. Automated StratusOCT output values showed poorer correlations than manually calculated OCTOR values. CONCLUSIONS: OCT features of CNV lesions as measured by manual quantitative subanalysis correlate better with angiographic parameters than values provided by the automated StratusOCT analysis. These measures may improve our understanding of the morphologic effects of CNV lesions and may facilitate the development of a hybrid FA and OCT-based classification system for future clinical trials, which more fully characterizes CNV lesions.

Contribution of D1R-expressing neurons of the dorsal dentate gyrus and Cav1.2 channels in extinction of cocaine conditioned place preference.

Cocaine-associated contextual cues can trigger relapse behavior by recruiting the hippocampus. Extinction of cocaine-associated contextual memories can reduce cocaine-seeking behavior, however the molecular mechanisms within the hippocampus that underlie contextual extinction behavior and subsequent reinstatement remain poorly understood. Here, we extend our previous findings for a role of Cav1.2 L-type Ca2+ channels in dopamine 1 receptor (D1R)-expressing cells in extinction of cocaine conditioned place preference (CPP) in adult male mice. We report that attenuated cocaine CPP extinction in mice lacking Cav1.2 channels in D1R-expressing cells (D1cre, Cav1.2fl/fl) can be rescued through chemogenetic activation of D1R-expressing cells within the dorsal dentate gyrus (dDG), but not the dorsal CA1 (dCA1). This is supported by the finding that Cav1.2 channels are required in excitatory cells of the dDG, but not in the dCA1, for cocaine CPP extinction. Examination of the role of S1928 phosphorylation of Cav1.2, a protein kinase A (PKA) site using S1928A Cav1.2 phosphomutant mice revealed no extinction deficit, likely due to homeostatic scaling up of extinction-dependent S845 GluA1 phosphorylation in the dDG. However, phosphomutant mice failed to show cocaine-primed reinstatement which can be reversed by chemogenetic manipulation of excitatory cells in the dDG during extinction training. These findings outline an essential role for the interaction between D1R, Cav1.2, and GluA1 signaling in the dDG for extinction of cocaine-associated contextual memories.

Effect of ranibizumab retreatment frequency on neurosensory retinal volume in neovascular amd.

PURPOSE: To determine the characteristics of patients with neovascular age-related macular degeneration who show initial anatomic improvements on optical coherence tomography in response to treatment with ranibizumab, but who subsequently regress toward their anatomic baseline. METHODS: Data from 50 consecutive patients, receiving ranibizumab therapy for neovascular age-related macular degeneration, were collected. Raw StratusOCT images were analyzed using custom software ("OCTOR"). Changes in volume of neurosensory retina at months 1, 3, and 6 were calculated. Baseline demographic and morphologic characteristics were compared. RESULTS: Forty-two patients (84%) showed a reduction in total retinal volume 1 month after initial treatment with ranibizumab. Of the patients that initially showed a reduction, 16 (38%) maintained this reduction through month 6, whereas 26 patients (62%) demonstrated a subsequent increase in retinal volume. Patients who maintained a reduction in edema received 3.75 +/- 1.18 injections of ranibizumab versus 2.96 +/- 1.34 injections for patients who did not (P = 0.049). Regression of initial anatomic improvements was associated with worsening of visual acuity (r = 0.599, P = 0.002). CONCLUSION: Patients receiving fewer injections of ranibizumab appeared less likely to maintain anatomic improvements achieved following commencement of ranibizumab therapy; regression of these improvements was associated with deterioration in visual acuity.

Relationship between optical coherence tomography retinal parameters and visual acuity in neovascular age-related macular degeneration.

PURPOSE: To investigate the relationship between optical coherence tomography (OCT)-derived measurements of retinal morphology and visual acuity in patients with neovascular age-related macular degeneration (AMD). DESIGN: Retrospective cross-sectional study. PARTICIPANTS: A total of 216 consecutive patients (216 eyes) newly diagnosed with neovascular AMD who underwent StratusOCT imaging at the time of diagnosis. METHODS: Best-corrected Snellen visual acuity was recorded for each patient. Raw exported StratusOCT images for each patient were analyzed using publicly available custom software entitled "OCTOR," which allows the precise positioning of prespecified boundaries on individual B-scans. Thickness and volume were calculated for morphologic parameters of interest: neurosensory retina, subretinal fluid, subretinal tissue (SRT), and pigment epithelial detachment. MAIN OUTCOME MEASURES: OCT-derived measurements of retinal morphology and visual acuity. RESULTS: An increased total volume of SRT was correlated with decreased visual acuity (r = 0.370, P<0.0001). Decreased visual acuity was also modestly correlated with increased thickness of the neurosensory retina at the foveal center point (r = 0.245, P = 0.0004). No statistically significant association was detected between visual acuity and the total volume of subretinal fluid or pigment epithelial detachment. The association between visual acuity and both the neurosensory retina and the SRT was stronger for lesions classified as minimally classic or occult on fluorescein angiography. For occult lesions, 20% of the variation in visual acuity could be predicted by a multiple regression model that incorporated age and SRT volume, whereas, for minimally classic lesions, 62% of the variation in visual acuity could be predicted by a multiple regression model that incorporated age, total neurosensory retinal volume, and total SRT volume. CONCLUSIONS: The presence of increased SRT thickness and volume on OCT, and to a lesser extent increased neurosensory retinal thickness and volume, is associated with decreased visual acuity in neovascular AMD. However, because of the complex pathophysiology of neovascular AMD and, in part, the limitations of StratusOCT, these factors only account for a small degree of the variation in visual acuity that these patients exhibit. The detection of stronger correlations between retinal anatomy and visual acuity is likely to require the use of more advanced imaging modalities. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Quantitative comparison of optical coherence tomography after pegaptanib or bevacizumab in neovascular age-related macular degeneration.

PURPOSE: To demonstrate the benefit of enhanced quantitative analysis of optical coherence tomography (OCT) images using computer-assisted grading to compare the short-term morphologic effects of pegaptanib and bevacizumab treatment for neovascular age-related macular degeneration (AMD). DESIGN: Retrospective consecutive case series. PARTICIPANTS: Fifty-three cases with neovascular AMD undergoing pegaptanib or bevacizumab therapy. METHODS: Fifty-three consecutive cases of patients who underwent StratusOCT imaging followed by treatment with either intravitreal pegaptanib (n = 18) or bevacizumab (n = 35) for neovascular AMD were retrospectively collected. Raw exported StratusOCT images were analyzed using publicly available custom software (OCTOR) designed to define the boundaries of various spaces manually. Changes in thickness and volume of the retina, subretinal fluid (SRF), subretinal tissue, and pigment epithelial detachments (PEDs) before treatment and at 3 months after treatment were calculated and compared between treatment groups. OCTOR software measurements after manual grading were also compared with the automated StratusOCT output. MAIN OUTCOME MEASURES: Volume and thickness measurements calculated by the automated StratusOCT software and the manual grading software OCTOR. RESULTS: Intravitreal bevacizumab resulted in a statistically significant greater reduction of total retinal volume than pegaptanib (-0.88+/-1.4 mm(3) vs. -0.07+/-0.5 mm(3), P = 0.003). Mean foveal central subfield (FCS) retinal volume decreased from 0.26+/-0.1 mm(3) to 0.21+/-0.1 mm(3) (P = 0.001) in the bevacizumab group and remained constant at 0.22+/-0.1 in the pegaptanib group 3 months after injection. Subanalysis of the SRF, subretinal tissue, and PEDs revealed statistically significant reductions of the total volume of all 3 spaces after bevacizumab injections but no significant change after pegaptanib treatment. Automated StratusOCT output measurements of FCS thickness, foveal center point thickness, and total volume of the retina did not reveal a statistically significant difference between the treatments. CONCLUSIONS: Differences in morphologic response between treatments were less apparent on automated StratusOCT output than on computer-assisted analysis. Although intravitreal bevacizumab was associated with a greater short-term reduction in features of exudation than pegaptanib therapy, the retrospective design of the study limits the significance of this finding. Computer-assisted subanalysis of OCT data, however, may be a useful tool in more precisely defining the anatomic effects of therapies for neovascular AMD.